To improve neoantigen prediction methods, Xia et al. conducted a systematic in silico analysis, buttressed with structural analysis and binding measurements, to identify and score HLA anchor positions for multiple alleles. With the assumption that central tolerance eliminates TCRs identifying the surface of wild-type peptide:HLA complexes, mutated neoantigen peptides with varying positions of the mutation in the peptide were categorized into different scenarios that differentially impacted that surface and would be favored or not to be immunogenic. Using positional information was predicted to significantly re-prioritize neoantigen ranking.
Contributed by Ed Fritsch
ABSTRACT: Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. Because most somatic mutations are single-nucleotide variants, changes between wild-type and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient's specific MHC molecules. Whereas a subset of peptide positions are presented to the T cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T cell responses. We computationally predicted anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6 to 38% of neoantigen candidates are potentially misclassified and can be rescued using allele-specific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline, and improve the identification process for relevant clinical studies.
Author Info: (1) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine
Author Info: (1) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (2) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (3) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (4) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (5) Pure Protein LLC, Oklahoma City, OK 73104, USA. (6) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (7) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (8) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. The Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. (9) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (10) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (11) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (12) Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (13) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (14) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (15) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (16) McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. (17) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (18) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (19) Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. (20) Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (21) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (22) Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. (23) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. (24) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. (25) Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
